Synthetic hormones for insect control

ABSTRACT

Ethers of open chain terpenoid compounds and their monoepoxides were synthesized and found to mimic the juvenile hormones of insects and to be extremely effective as insect control agents.

United States Patent Related U.S. Application Data U.S. Cl. 424/278; 424/DIG. l2; 260/340.9;

260/348 R Int. Cl. A01N 9/28 Field of Search 424/278, DIG. 12, 282; 26O/34O.9, 348

Bowers Sept. 23, 1975 SYNTHETIC HORMONES FOR INSECT [56] 4 References Cited CONTROL UNITED STATES PATENTS [75] Inventor: William S. Bowers, Geneva, N.Y. 3,655,700 4/1972 Siddall 260/340.5

. 3,681,385 8/l972 Siddall 424/278 [73] Ass'gnee- The Umted States Amer'ca as 3,766,220 10/1973 Jarolim et aL 424/278 represented by the Secretary of 7 Agriculture, Washington, DC. OTHER PUBLICATIONS [22] Filed: Aug 22 1974 Borkovec, A., Insect Chemosterilants, Vol. VII

7 (1966), Pp- 61-63. [21] Appl. N0.: 499,690

Primary Examiner-V. D. Turner Attorney, Agent, or Firm-M. Howard Silverstein; Max D. Hensley; William E. Scott [5 7] ABSTRACT Ethers of open chain terpenoid compounds and their monoepoxides were synthesized and found to mimic the juvenile hormones of insects and to be extremely effective as insect control agents.

6 Claims, No Drawings SYNTHETIC HORMONES FOR INSECT CONTROL This application is a division of application Ser. No. 363,295,.- filed May 23, 1973, now U.S. Pat. No. 3,852,472 which is in turn a division of application Ser. No. 78,577, filed Oct. 6, 1970, .now abandoned.

This invention relates to insect control and more particularly to compounds and to the preparation of compounds that have high juvenile hormone activity and which are highly ovicidal to insect eggs.

There is considerable concern throughout the' world about the persistence of many insecticides and insecticide residues in our environment and the potential ha- Zard that these materials represent to human populations. In addition, many species of insect pests have become resistant or immune to many of the insecticides on the market. Thus, more selective chemicals are required which will not pose a' threat to human populations and to which the insects will not develop resistance.

The compounds of the present invention should be suitable replacements for the insecticides now being used to control-stored product insects'and many social pests such as fireants and termites. In addition, it may be feasible to'use" these compounds in field applications to coiitrol'awide variety of insects, the toxicity of the compounds to vertebrates should be insignificant, and the cost of produce them commercially should be very competitive with that of well known insecticides.

One object of this invention is to provide a means for achieving selective, safe, economical control of insect pests.

Another object is to provide chemical compounds that prevent insect maturation when applied topically,

when fed to insects or when applied in a vapor state as a fumigant, to an insect in an immature stage of growth.

A further object of this invention is to provide compounds that adversely affec tthe biological function of insects, particularly their ability to mature to an adult stage.

In general, according to t hie present invention the terpenoid ethers and their corresponding epoxides are synthesized and found to prevent 'insecthma'turation when applied to immature stages of several species of insects by topical application, by feeding or by fumigation (exposure to vapor). Thus an immature insect exposed to these compounds is unable to metamorphose into a normal adult. Topical application of as little as 10.0 nanograms (0.0l #g) of the more active com-- pound s in this serics is sufficientto prevent metamorl "YtcH-inC Ht'uuI-o-z wherein Y is RC=CH or R \-CH,

.-R is a straight chain alkyl containing from l-2 carbon in which n is 0-3. 4 The terpenoid portions of the compounds were pre- 30 pared in part by the Marc Julia synthesis [Bull. Soc.

Chem. France 1072, (1960)] as outlined below.

Oxidation was performed with chromic acid solution in acetone [1. Chem. Soc'. 2548(l953)] v phosis T he insect which e merges from the treated pupa retains iinrnature genitalia whichpreclude copulation and X'BPIZOdUQIiOfl. The insects die shortly, after I molting to thi adultoidcondition. Also, when .used as a vapor or asa dip treatment for eggs the compounds drastically reduce egg hatch. a v

The compounds of this invention having the following general formula.

The vinyl alcohols are prepared by the grignard reac- 60 tion with vinyl magnesium bromide (or chloride) in tetrahydrofuran.

The vinyl alcohols were converted to the allylic bromides by treatment with hydrogen bromide in aqueous or acetic acid solution. Thus, an aliquot of the vinyl alcohol was added dropwise to a rapidly stirred ice cold aqueous or acetic acid solution containing 2 molar equivalents of hydrogen bromide. When addition was complete, stirring was continued for 20 minutes and then the reaction mixture was poured into an excess of ice cold sodium carbonate solution. extracted with diethyl ether and washed to neutrality with water. After drying the ethereal extracts over sodium sulfate andremoval of the solvent in vacuo, the allylic bromides were obtained in nearly quantitative yield. 1

Compounds of the general formula wherein Y is H I H R is a straight chain alkyl containing from 1 to 2 carbon atoms such as CH CH -,CH

x is a number from 1 to 2; and

A is CH CH O(CH CH or hzlsc The crude ethers obtained from the foregoing reactions were purified by chromatography over florisil. The crude material was put on a florisil column (30 gm florisil/gm crude material) in hexane and eluted stepwise with increasing concentrations of diethyl ether in hexane. Purity was determined by gas-liquid chromatography and infra-red spectroscopy to be greater than 99%.

Compounds of the general formula wherein Y is ' CH3 CH R is a straight chain alkyl containg from 1-2 carbon atoms such as CH CH CH x is a number from 1 to 2; and

E is CH COO(CH ),,CH

in which n is 0 to 1 i were prepared from the terpenoid alcohols. The allylic terpen oid alcohols were preparedfrom their corresponding vinyl analogs by chromic acid oxidation [1. Chem; Soc. 2548 (1953)] to the conjugated aldehyde, followed by'reduction to the primary alcohol with a metal hydride such as sodium borohydride in methanol, or lithium aluminum hydride in ether.

The primary halides of E, (Br CH COQ (CH CH or were coupled with the terpenoid alcohols under basic conditions in a reaction bomb, under reflux, or by stirring at room temperature for an extended period of time.

The crude ethers were purified by chromatographyv over florisil as previously described. Purity was determined by gas-liquid chromatography and infra-red spectroscopy to be greater than 99%.

Compounds of the general structure wherein Y is CH R 2 HCl The reaction was complete in 1 hour and the reaction mixture was extracted with diethyl ether and washed ride during the addition of a slight molar excess of an epoxidizing agent such as m-chloro perbenzoic acid.

Epoxidation occurred selectively at the terminal double bond within a few minutes to one hour. The reaction mixture was washed with 5% sodium carbonate and then with water to neutrality, and dried over sodium sulfate. Solvent was removed in vacuo.

The epoxides were purified by chromatography over florisil as previously described.

Purity was ascertained by gas-liquid chromatography and infrared spectroscopy to be greater than 99%.

The compounds and their epoxides prepared by the above procedures are shown in Table 1.

Although the general procedures just described are undoubtedly adequate for those skilled in thea'rt, the

following examples further illustrate the preparation of compounds within the scope of each of the general structures shown above.

Synthesis of Compound 49 in Table l In a 500 ml. boiling flask, 10.8 g. ethylene glycol butyl ether, was combined with 10.2 g. potassium tertbutoxide and 10 g. geranyl bromide in 100 ml. dimethoxyethane. The reaction mixture was stirred at room temperature for 16 hrs. and then poured into 200 ml. of hexane and washed 2X with water and 1X with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and the hexane removed in vacuo. 13.6 g. of crude compound wasrecovered and found to be suitable for the subsequent epoxidation.

Epoxidation of Compound 49 in Table l successively with 5% aqueous sodium carbonate and Wow-noun.

Dissolved 4 g. of the Compound 49 in 50 ml. CH CI and with stirring added 3.2 g. m-chloroperbenzoic acid in aliquots. Stirred 30 min. and then made the solution basic with 10% aqueous sodium carbonate. Stripped off the solvent in vacuo. Residue was dissolved in diethyl ether and washed in a separatory funnel with 10% sodium carbonate 2X, and water 2X. Dried organic layer over anhydrous sodium sulfate. Stripped off solventin vacuo. Crude epoxide yield was 3.8 gm. Fractionation of the crude epoxide over 60 gm. of florisil by stepwise elution with increasing concentrations of diethyl ether in hexane gave 3.0 g. pure epoxide. (Compound No.

Combined gm. glycerol acctonidc and 5.4 gm. potassium tert-butoxide in 50 ml. dimethoxyethane and stirred for min. Added 8.2 g. geranyl bromide and continued stirring at room temperature for 16 hrs. Filtered, stripped off dimethoxyethane, dissolved residue in diethyl ether and washed with water in a separatory funnel 3X. Dried organic layer over anhydrous sodium sulfate and stripped off solvent in ether. Crude ether Compound 65 yield was 6.7 gm.

3 gm. of Compound 65 was fractionated by column chromatography over 70 gm. of florisil. Stepwise elution with increasing concentrations of diethyl ether in hexane gave 1.9 g. of pure Compound 65.

Epoxidation of Compound 65 in Table 11 Dissolved 1.3 g. of Compound 65 in ml. CH Cl and added in aliquots 1.0 gm. of m-Chloroperbenzoic acid. Reaction stirred 30 min. Solution made basic with 10% aqueous sodium carbonate. Stripped off solvent in vacuo. Residue dissolved in diethyl ether and washed in a separatory funnel with 10% sodium carbonate 2X and with water 2X. Dried over anhydrous sodium sulfate. Crude epoxide, Compound 73, was 1.3 g. The crude epoxide was fractionated by column chromatography as specified for Compound 65. Yield of pure epoxide, Compound 73, was 950 mg. (Compound 73) Synthesis of Compound 81 in Table l W urcngqoocit,

W OCH-:COOCHn Stirred 5 gm geraniol with 3.5 gm. potassium tertiutoxide in 50 ml. dimethoxyethane for 30 minutes. \dded to above 5.8 g. of methyl bromoacetate and tirred at room temperature for 16 hrs. Reaction mix-' ure dissolved in 200 ml. diethyl ether and washed in a eparatory funnel with water 3X. Organic layer dried 8 over anhydrous sodium sulfate. Stripped off solvent in vacuo. Yield of crude Compound 81 was 7.3 gm.

The crude ether was chromatographed on a column containing 150 gm. of florisil. Elution with increasing concentrations of diethyl ether in hexane gave a pure fraction containing 1.4 gm. of Compound 81.

Epoxidation of Compound 89 in jTable l AWOCHECOOCH,

Wbcmcoocu.

ice bath was maintained for 15 min. Sodium sulfite was added to destroy any excess peracid. The reaction mixture was dissolved in about 200 ml. of diethyl ether and washed in a separatory funnel with 10% aqueous sodium carbonate 2X and water 2X. Organic layer was dried over anhydrous sodium sulfate and the solvent stripped off in vacuo. Yield of crude Compound 89 was 1.26 gm. i l

The crude Compound 89 was fractionated over 30 gm. of florisil as specified for Compound 81 and 770 mg. of pure Compound 89 was obtained. Analysis by gaschromatography and infrared. (Compound 89) Synthesis of Compound 1 13 in Table l Dissolved 5 g. geraniol in 50 ml. dimethoxyethane containing 3.5 g. potassium tert-butoxide with stirring for 30 min. Added 4.4 g. epibromohydrin and stirred at room temperature for 3 hrs. Filtered, dissolved in about 250 ml. diethyl ether and washed with water 3X in a separatory funnel. The organic layer was dried over anhydrous sodium sulfate and the solvent stripped off in vacuo. Yield of crude ether was 7.6 gm. The crude ether was fractionated by column chromatography over gm. of florisil. Stepwise elution with increasing concentrations of ether in hexane gave 2.24 gm. of pure Compound 113.

Epoxidation of Compound 1 13 in Table l Dissolved 2.24 g. of Compound 113 in 50 ml. CH Cl and with stirring added 2.2 g. m-chloroperbenzoic acid in aliquots. Stirred an additional 30 min., made basic with 10% aqueous sodium carbonate, dissolved in 200 ml. diethyl ether and washed with 10% aqueous sodium carbonate 2X and with water 2X in a separatory fu nncl.

diethyl ether in.hexane gave 713 mg. of pure Com-- pound 121. Analysis by gas-chromatography. and infrared. (Compound 121) Synthesis of Compound 145 in Table I Geraniol (10 gm.) in 25 'ml. diethyl ether was added dropwise to 14 g. ethyl vinyl ether containing 1 drop of concentrated HCl. After addition, stirring was maintained for 2 hrs. in a warm water bath (ca. 50C.).

The reaction mixture was dissolved in .200 ml. of di ethyl ether and washed in a separatory funnel with 5% aqueous sodium carbonate IX, and water 3X. The organic layer was dried over anhydrous sodium sulfate. The solvent was stripped off in vacuo. The crude acetal yield was 14.5 gm.

Filtration of 5 gm. of the acetal in hexane through a column containing 150 gm. of florisil gave a quantitative return of 5 gm. of pure acetal Compound 145. Purity ascertained by gas-chromatography and infrared analysis.

Epoxidation of Compound 145 in Table l To a stirred solution of 5gm of Compound 145 in 100 ml. hexane was added drop wise 4.94 gm. mchloroperbenzoic acid dissolved ml. CH Cl After addition, stirring was coiitiriud'fo'r '20 min. Excess peracid was destroyed with sodium sulfite. The reaction mixture was made basic with 5% aqueous potassiur'n'hydroxide' and the sQlvehts'tripped off in vacuo.

Theresidue was dissolved in diethyl ether and washed in a separatory funnel with 5% aqueous potassium hydroxide. 1X and with water-3 2$ I Organic layer was dried o'vei"ari hydrous'sod'ium sulfate and the solvent stripped off in vacuo. Yield of crude Compound 153 was 5T0 gm.

Fractionization of -5.0 'gri lof Compound-1S3 by column chromatography over 100 gm. of florisil by stepwise elution with increasing concentrations of diethyl ether in hexane gave 3.0 gm. of pure Compound 153. Analysis by gas-chromatography and infrared. (Compound 153 The morphogenetic effects of "some of the compounds in the Tenebrio genitalia assay (Life Sciences 4, 2323-31, 1965) are shown in Table I1. Y

' Topical application to Tenebrio, ,pupae of as little as v Topical application of'somewhat greater amounts of compounds 76, 89, 121, 153, were required to induce retention of pupal genitalia and/or produce pupal-adult intermediates in Tenebrio. In all cases the affected insects were unable to form normal adults and died during or shortly after their ultimate molt without significant feeding and without any reproduction.

Table III shows the effects of compounds 25, 26, 28,

57, 73, 81, 89, 153, on the Mexican bean beetle. Topical application of nanogram tomicrogram quantities of these compounds prevents normal adult development and the insects die during the ultimate molt. Topical treatment of Mexican bean beetle eggs with extremely dilute acetone solutions of thesecornpounds c'aused severe reduction in egg hatch.-.

Table IV shows the morphogenetic effects of compounds 25, 26,28, 57, 73, 89, 121, 153, on Tenebrio after exposure of the pupae to the vapors of these com pounds. These results exemplify the potential use of the compounds as fumigants.

T LE- 1 Synthesized Tcrpcnoid Ethcrs and Their Epoxidcs TABLE 1- Continued Synthcsizud Tcrpcnnid Ether s and Thcir Epnxidcs o-cH cH I)? (H m-1,,

TABLE I C0ntinued Synthesized Tcrpcnoid Ethcrs and Their Epoxidcs TABLE l-("onlinucd TABLE 1- Continued Synthesized Tcrpcnuid i'ilhurs and Their Epuxidcs Synlhcsi/cd Tcrpcnoid Elhcrs and Their Epnxidcs Woman owlmuvnfi 0 (X11 11 0mm; n1;

Womb-CH owl-12mm Mm'ulj'll in Worn! n,

;;TABLE l-Cominuad TABLE I Continued Synthesized Tcrpcnoid Ethcrs and-Their Epoxidcs Synthesized TcrpcnuidI-Ithcrs and Their Epuxidcs if V ()CHQC OC i OCHi-OCH m h a H w w m 0 0 E H H H C cv C 0 0 1 o o 5 6 7 9 9 5 0 5 4 5 5 m H I H H C OIF. HP. fir. H H ,L C O O O 7 o 0 I Z on on 8 IOU WTABLE I Table II Synthesized Tcrpcnoid Ethcrs and Their Epoxidcs Morphogenetic Effects of Representative Compounds in L Y t the 'I'enehrin Genitalia Assay H Compound Micrograms of Compound Required to 1 Numher' Produce the indicated Morphogenetic ElTects' 1(1'). O HOCH ,CH CH;. in Pupal-Adult I Table l Intermediates Pupal Genitalia 2 ('H.. 25 t 0.1 r 0.01 2 W A OCHCHH 26 0.1 0.01 11. o. 'H- 2 2 :1 28 0.1 0.01 '57 0.1 0.01 73 0.1 0.01 76 1.0 0.1

Z- 89 100.0 1.0 H14 ()(H()( H= =1 121 100.0 1.0 153 100.0 10.0 I cH.

H. I66 Nola-001.111.6113

Each ol the zihove morphogentic el'l'ects causes the insect to die shortly ther e'afte I V Table Ill 2 j. v

I67 0 H-()( HECHQCHZ! Reduction in Adult. Emergence and Egg Hatch of Mexican Bean Beetle Epilai'lma i'arirestis Compound Micrograms of Compound PPM of Compound CH: Required to cause 9071 Required to cause A Number in Reduction in adult 90% Reduction in 168 O 'H-OCHgCHgC a Table l Emergence Egg Hatch 2 25 ,0.1 i 1.0 Z6 0.1 10.0 E 214 0.01 1.0 109 Mo H OCH- C H:1 :88 0 81 10.0 100.0 4 89 100.0 100.0 1 153 0.1 1.0 170 o H-OCH CH CH 3 5 Topical treatment of 2-day old prepupae with on acetone solution of compound.

Topical treatment by dipping egg masses in an acetone solution of compound.

"An acetone control conducted for each of the above treatments showed that the 1 Hit solvent contributed nothing to the effect o1- the compounds 171 ()CH ()CH:CH- CH;;

Table IV Morphogentic Effects of Representative Compounds on 172 O H-()CH .CH CH Tem'hrio pupae hy Fumigation.

. Compound Micrograms of Compound Required to 0 Produce Pupal-Gcnitalia and Pupal- Number in Adult intermediates by Vapor Expo- Tahle 1 sure i1 25 0.1 5.0 173 o O H-OCH CH C'H 26 0.1 5.0 28 0.1 5.0 57 0.1 5.0 73 0.1 5.0 89 0.1 5.0 H 121 1.0 10.0 j 153 1.0 10.0 174 o O 'H-OC'H-l'H-fll'l Compounds were spread over the lid of a rm diameter petri dish in a small volume of acetone an after evaporation of the acetone the lid was placed over the bottom of the petri dish containing newly molted Twu-hriu pupae. The pupae were therefore exposed only to the vaporsand did not come in contact with the CH compound directly. The insects were left in the dish until they underwent the final 3 molt toward the adult. 175 o OCH- ()C lI C 1- H;1

6O I claim:

1. A method of controlling the maturation of insects CH selected from the group consisting of Tenebrio molitor I (L.) and EpiIac/ma varivestis comprising contacting 1 ()CH- (X'HQCH-L'H O said Insects at an immature stage of growth with an cf- 65 fcctive maturation inhibiting amount of a compound of the formula CH3 R wherein o t R and R are straight chain alkyls containing from I to 2 carbon atoms; x is a number from l'to 2; and Z is selected from the group consisting of 24 6. A method of preventing the hatching of eggs of insects selected from the group consisting Tenebrio malilor (L.) EpiIac/ma varivestis comprising applying to said insect eggs an effective egg hatch preventive amount of a compound of the formula CH R wherein R and R are straight chain alkyls containing from 1 to 2 carbon atoms; x is a number from 1 to 2; and Z is selected from the group consisting of 

1. A METHOD OF CONTROLLING THE MATURATION OF INSECTS SELECTED FROM THE GROUP CONSISTING OF TENEBRIO MOLITOR (L.) AND EPILACHNA VARIVESTIS COMPRISING CONTACTING SAID INSECTS AT AN IMMATURE STAGE OF GROWTH WITH AN EFFECTIVE MATURATION INHIBITING AMOUNT OF A COMPOUND OF THE FORMULA
 2. The method of claim 1 in which the compound is applied topically.
 3. The method of claim 1 in which the compound is applied as a fumigant.
 4. The method of claim 1 in which the compound is applied orally.
 5. The method of claim 1 in which the compound is applied as a solute in acetone.
 6. A method of preventing the hatching of eggs of insects selected from the group consisting Tenebrio molitor (L.) Epilachna varivestis comprising applying to said insect eggs an effective egg hatch preventive amount of a compound of the formula 